We are interested primarily in the specific susceptibility of motor neurons to Amyotrophic Lateral Sclerosis (ALS). ALS results in selective degeneration of motor neurons despite that factors contributing to ALS are also present in other CNS neurons that are generally resistant to ALS. Even among motor neurons there are differing degrees of susceptibility to ALS. For example, cranial nerve nuclei Ill, IV, and VI in the brainstem are relatively resistant to ALS, while facial nucleus motor neurons inevitably succumb to degeneration. Since only subsets of neurons degenerate in ALS, we hypothesize that there may be specific features of motor neurons that confer susceptibility. Identification and characterization of unique molecules that either diminish or enhance a motor neuron's vulnerability to degeneration are critical to understanding and eventually treating motor neuron diseases. Along these lines, knowledge of the gene and protein expression profiles of a specific motor neuron group is critical to understanding their susceptibility to the effects of motor neuron disease. Therefore, we propose to identify genes uniquely expressed in cranial motor neurons by gene profiling using microarray and real-time PCR methods in normal and Cu/Zn superoxide dismutase (SOD1) mutant mice, a mouse model of ALS. Such a study will allow us to understand the molecular architecture and function specific to motor neurons and also will establish a screening system for studying gene expression alterations in motor neuron diseases. The Specific Aims of this study are outlined below. Specific Aim 1. To identify motor neuron-specific gene expression by gene profiling. We will undertake cell sorting and laser capture microdissection to isolate mRNAs expressed in motor neurons of cranial motor nuclei. The genes expressed specifically in motor neurons will be identified and compared in normal and SOD1 mutant mice by DNA microarray and real-time PCR. Specific Aim 2. To define differential expression of motor neuron-specific genes in cranial motor nuclei of normal and SOD1 mutant mice. We will determine by in situ hybridization the expression patterns of motor neuron-specific genes in cranial motor nuclei identified in Specific Aim 1. Differential expression levels of these genes will be further quantified by real-time PCR.